tbuckley/cabot-search huggingface dataset:
The Gastric Cancer Registry Genome Explorer: A tool for genomic discovery.
Authors: Alison Figueroa Almeda, Susan M. Grimes, Giwon Shin, Hojoon Lee, Ignacio Alberto Wichmann, Stephanie Greer, Hanlee P. Ji
Journal: Journal of Clinical Oncology (2023)

434 Background: The Gastric Cancer Registry (GCR) collects clinical questionnaire data and biospecimens from gastric cancer (GC) patients and individuals at high risk for GC (through family history of GC or a germline CDH1 mutation). Its purpose is to facilitate research into better detection and treatment strategies for GC. In 2020, the GCR Genome Explorer (GCR-GE), a publicly accessible and interactive database of clinical and genomic data, was launched to meet this goal. Methods: We generated genomic datasets from participants when GC status and archival gastric tumor tissue were available. We processed the tumor tissue (and paired normal tissue when possible) for whole genome, whole exome, and bulk RNA sequencing. The following genomic features were identified: copy number variations, gene mutations, gene expression, microbiome composition, estimation of tumor-infiltrating immune cells, and tumor neoantigens. We populated (1) all genomic alterations identified from GCR sequencing data, and (2) demographic and pathologic data regarding the tumor that were compiled from participant questionnaires and medical records into the GCR-GE. In addition, sequencing files from the Cancer Genome Atlas (TCGA) were similarly analyzed and uploaded as external datasets. Features of the GCR-GE include cross-study comparisons, study summaries, and queries down to the individual gene, neoantigen, and patient level. Results: In total, 243 GC patients donated tumor samples. The new GCR-GE release contains genomic datasets for 214 of these tumors, as well as datasets for 443 gastric tumors and 185 esophageal tumors from TCGA. Data generation was possible thanks to 756 subjects who enrolled in the GCR from 2011-2022. Most subjects were diagnosed with GC only (N=487), but interestingly, some met multiple criteria. For instance, 10 GC patients had a family history; 10 had a germline CDH1 mutation; and 21 patients had GC, a family history, and a germline CDH1 mutation. Efforts to upload additional datasets are ongoing. All data in the GCR-GE is downloadable. Conclusions: The GCR-GE is a comprehensive resource of genomic and clinical data. Given its accessibility, ease of use, and large cohort sizes, the GCR-GE presents a highly valuable tool for accelerating GC research.
Pretreatment risk prediction for distant metastasis in locally advanced rectal cancer.
Authors: Changhoon Song, Byung-Hee Kang, Jae-Sung Kim
Journal: Journal of Clinical Oncology (2023)

248 Background: Distant metastasis is the most common form of recurrence in locally advanced rectal cancer. This study aimed to identify pretreatment risk factors for distant metastases in patients with locally advanced rectal cancer. Methods: This single-institution retrospective study included 285 patients who underwent preoperative chemoradiotherapy followed by surgical resection between January 2016 and December 2020. Pretreatment clinical characteristics, MRI findings, and blood profiles were analyzed to investigate its association with distant metastasis. Results: With a median follow-up of 39 months (range: 6 - 78), 42 patients had confirmed distant metastasis (14.7%), and most distant metastasis occurred within three years (40 patients, 95.2%). In the multivariate analysis, pretreatment extramural venous invasion (EMVI, HR = 3.05, p &lt; 0.001) and carcinoembryonic antigen (CEA) &gt; 10 ng/mL (HR = 2.77, p = 0.002) were independent predictors of distant metastasis. Patients with no adverse factors had significantly better distant metastasis-free survival than patients with 1 or 2 adverse features (92% vs. 70% vs. 59% (p &lt; 0.001) at 3 years). Conclusions: Pretreatment CEA and EMVI have predictive significance for distant metastasis in locally advanced rectal cancer. Our findings may help select patients who may benefit from intensified preoperative treatment, such as total neoadjuvant therapy.
The prognostic value of C-reactive protein/albumin ratio and platelet-lymphocyte ratio in patients with pancreatic cancer.
Authors: Yang-Chen Shen, Chi-Hsiang Chu, Po-See Chen, Cheng-Feng Lin, Ping-Yen Liu, Peng-Chan Lin, Chia-Jui Yen, Yan-Shen Shan
Journal: Journal of Clinical Oncology (2023)

678 Background: Pancreatic cancer is a highly malignant tumor with poor prognosis. Therefore, identification of prognostic markers is very crucial for improved risk stratification in pancreatic cancer patients. Although various systemic inflammatory markers have been investigated for their prognostic roles in pancreatic cancer, inconsistent results have been found across studies. Accordingly, the present study aimed to identify the prognostic value of inflammatory markers for patients with pancreatic cancer. Methods: The study enrolled 185 patients with pancreatic cancer. The inflammatory markers, namely, the modified Glasgow Prognostic Score (mGPS), the prognostic nutritional index (PNI), the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), the C-reactive protein (CRP)/albumin ratio (CAR), the platelet/albumin ratio (PAR), and the CRP/lymphocyte ratio (CLR), were evaluated. Receiver operating characteristics curve analysis was performed to determine the cut-off values. The Cox proportional hazards model was used to analyze the factors affecting the prognosis. Results: The mean age of the patients was 64.1 years (with a standard deviation of 11.1), and their average overall survival (OS) was 10.5 months (95% confidence interval [CI] = 9.7–11.4). In the univariate analysis, metastatic disease, carbohydrate antigen (CA)19-9, mGPS, PNI, NLR, PLR, CAR, and CLR were significantly associated with OS ( P&lt; 0.05). In the multivariate analysis, metastatic diseases (hazard ratio [HR] = 2.52, 95% CI = 1.03–6.15, P = 0.04), CA19-9 (HR = 3.96, 95% CI = 2.01–7.79, P&lt; 0.001), PLR (HR = 2.37, 95% CI = 1.11–5.04, P = 0.03), and CAR (HR = 4.45, 95% CI = 2.19–9.03, P &lt; 0.001) were identified as independent prognostic factors for OS. Conclusions: Pretreatment PLR, CAR, CA 19-9 , and metastatic diseases were found to be independent indicators of poor prognosis in patients with pancreatic cancer. We believe that our findings will shed light on the identification of prognostic factors, which might enable a better risk stratification in pancreatic cancer patients.
Feasibility of implantable microdosing devices to perform in vivo pharmacotyping in pancreatic cancer.
Authors: Lyudmyla Demyan, Oliver Standring, Taemoon Chung, Emma Gazzara, Scott Lyons, Matthew John Weiss, Youngkyu Park, Oliver Jonas, David A. Tuveson, Daniel King
Journal: Journal of Clinical Oncology (2023)

742 Background: Current biomarkers offer modest predictive capacity for drug sensitivity testing in pancreatic cancer. Patient-specific pharmacotyping offers the potential for a more direct, personalized prediction model. Recently, an implantable microdevice was developed to facilitate in situ multi-agent pharmacotyping and has since entered clinical trials in multiple cancer types, but had not yet been tested in pancreatic cancer. Here we evaluated the use of a microdosing device (microdevice) in a mouse xenotransplant model of pancreatic cancer as proof of principle to inform future translation to the clinic. Methods: A microdevice consists of a cylindrical frame and 18 wells embedded with standard chemotherapy agents (5 FU, gemcitabine, SN 38, paclitaxel, oxaliplatin), a non-toxic polyethylene glycol (PEG) matrix as control, and doxorubicin, the auto-fluorescent properties of which allow us to determine the distance of drug diffusion for each tumor. Devices were implanted into murine xenotransplanted human organoids (hM1A and hM1E Table 1). Microdevices retrieved at 4h, 8h, and 24h post-implantation together with tumors were fixed in 10% formalin. The tissue was embedded in paraffin and sectioned parallel to the device. A distance-dependent drug diffusion rate and concentration profiles with doxorubicin were evaluated. Co-immunohistochemistry (IHC) for cleaved caspase-3 (CC3), gamma H2AX (apoptosis markers), and human mitochondria (human cancer cell marker) was performed in the area of drug diffusion to determine the cytotoxic effects of chemotherapy. Results: 15 animals were enrolled in the experiment with 100% postoperative survival. One device per animal was placed, and all devices were successfully retrieved. Microdevice insertion and exposure to PEG had no effect on tumor integrity. At 250-350µm from the well, we observed intensity from doxorubicin, suggesting drug diffusion. The signal on differential response to drugs was detected as early as 4 hours. Conclusions: Utilization of implantable microdevice to predictcancer drug sensitivity is feasible in organoid transplantation animal models of pancreatic cancer. Future work is needed to expand this model to other cancer drugs and biomarkers to evaluate the cancer drug sensitivity and to test the feasibility of this model to study the effects of chemotherapy on the tumor microenvironment. [Table: see text]
Immunohistochemistry-based molecular classification of gastric cancer in India: How are we different?
Authors: Biswajit Dubashi, Charles L, Yadav Nisha, Rajesh Nachiappa Ganesh, Vikram Kate, Prasanth Penumadu, Sandhiya Selvarajan, Kalayarasan Raja, Smita Kayal, Prasanth Ganesan
Journal: Journal of Clinical Oncology (2023)

462 Background: TCGA and ACRG have classified gastric cancer (GC) into molecular subgroups using genomics. We attempted to classify GC from our region using IHC (Immunohistochemistry) to understand its prognostic significance and compare with similar data from other parts of the world. Methods: This was a retrospective cohort of GC patients from years 2017-18. EBV (LMP), MSI (MLH1, MSH2, PMS2, MSH6),p53, E-cadherin and PIK3CA were assessed by IHC. Clinicopathological characteristics and survival were evaluated for association with molecular subtypes as defined by TCGA and ACRG classification system. Results: A total of 191patients were included with EBV positivity 35 (18.3 %), MSI 33(17.3 %), p-53 aberration 25(13.1%), E-cadherin negative (29.3%). On univariate analysis, p53 aberration was associated with higher age (&gt;60 yrs), E- cadherin negative with diffuse histology &amp; antro-pyloric region as predominant site. MSI with intestinal histology &amp; antro-pyloric region as predominant site with MSI. The TCGA classification revealed EBV 35 (18%), MSI 28 (15 % ), GS 48 (25 %) and CIN 80 (42% ) subtypes respectively. CIN subtype was seen predominantly above 40 yrs of age (P=0.04), GS subtype was frequently associated with diffuse histology P&lt;0.0001. The ACRG classification revealed MSI 33(17%), MSS/EMT 51 (26.7%), MSS/ p53 normal 91 (47.6%) and MSS/p53 aberrant 16 (8.4) subtypes. MSS/E-cad- subtype was associated with diffuse histology. PIK3CA positivity was higher in CIN (TCGA )&amp; MSI (dmr) (ACRG) respectively. The median OS in MSI was 35 and 32 months higher compared to other subtypes (P&lt;0.0001) in TCGA and ACRG classification respectively. Conclusions: The TCGA and ACRG classification identified molecular subtypes based on IHC from our region and significantly correlated with clinical factors and survival. PIK3CA as an additional marker may be further explored to be included in the classification system. Abbreviation: EBV - Epstein–Barr-virus, MSI – Microsatellite-Instability, GS- Genomic-instability, CIN- Chromosomal-instability, MSS- Microsatellite-stable, EMT-Epithelial-mesenchymal-transition.[Table: see text]
Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations.
Authors: Anthony W. Tolcher, Wungki Park, Judy S. Wang, Alexander I. Spira, Pasi A. Janne, Ho-Jin Lee, Stanley Gill, Patricia LoRusso, Benjamin Herzberg, Jonathan W. Goldman, Daniel Morgensztern, Jordan Berlin, Anup Kasi, Hisaki Fujii, Meredith Pelster
Journal: Journal of Clinical Oncology (2023)

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 ubiquitin ligase proteins. In preclinical studies, ASP3082 selectively degraded the KRAS G12D-mutated protein and showed growth inhibitory activity in KRAS G12D-mutated cancer cells but not in KRAS -wildtype cancer cells. Notable antitumor effects of ASP3082 have been demonstrated when intravenously administered weekly in mice xenografted with KRAS G12D-mutated cancer cells. Methods: This first-in-human, open-label, multicenter, phase 1 study evaluates the safety and tolerability of ASP3082 in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer or other solid tumors. Participants with unresectable, locally advanced, or metastatic solid tumor malignancy with documented KRAS G12D mutation are eligible for enrollment. Part 1 consists of dose-escalation cohorts of 3−12 patients receiving intravenous administration of ASP3082 in a 21-day cycle. Part 2 consists of random assignment of ≤20 patients into 2 cohorts with different ASP3082 dose levels to determine the recommended phase 2 dose. Additional tumor-specific expansion cohorts may enroll ≤20 participants per tumor type. Primary endpoints will evaluate safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and Eastern Cooperative Oncology Group performance status. Secondary endpoints will evaluate objective response rate, duration of response, disease control rate per Response Evaluation Criteria in Solid Tumors version 1.1, pharmacokinetics of single and repeated doses of ASP3082, and changes in KRAS G12D in tumor samples. Exploratory objectives will evaluate potential biomarkers that may correlate with treatment outcomes. Tumor assessment follow-up will continue for ≤45 weeks or until progressive disease. Enrollment in Cohort 1 is complete, and enrollment to Cohort 2 began in September 2022. Clinical trial information: NCT05382559 .
Health-related quality of life (HRQoL) impact of lenvatinib (len) plus pembrolizumab (pembro) versus len plus placebo (pbo) as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC): Phase 3 LEAP-002 study.
Authors: Josep M Llovet, Masatoshi Kudo, Philippe Merle, Tim Meyer, Shukui Qin, Masafumi Ikeda, Ruocai Xu, Julien Edeline, Baek-Yeol Ryoo, Zhenggang Ren, Ann-Lii Cheng, Peter R Galle, Shuichi Kaneko, Hiromitsu Kumada, Shital Kamble, Josephine M Norquist, Kalgi Mody, Leonid Dubrovsky, Abby B. Siegel, Richard S. Finn
Journal: Journal of Clinical Oncology (2023)

506 Background: In LEAP-002 (NCT03713593), len + pembro achieved a median OS of 21.2 mo vs 19.0 mo with len + pbo with manageable safety in both arms in 1L aHCC, although the significance thresholds for OS and PFS were not met. We present here the results of prespecified exploratory patient (pt)-reported outcomes (PROs). Methods: 794 pts were randomized. PROs were assessed by EORTC QLQ-C30, EuroQol-5D5L (EQ5D-5L), and EORTC QLQ-HCC18 questionnaires. Analysis population for HRQoL endpoints included pts who received ≥1 dose of study Tx and completed ≥1 HRQoL assessment. Least squares mean (LSM) score changes from baseline (BL) to wk 27 were compared using a constrained longitudinal data analysis model (covariates: Tx, time, Tx by time interaction, and stratification factors). Kaplan-Meier method was used to estimate time to deterioration (TTD, time to 1st onset of ≥10 [out of 100] deterioration from BL in a given scale or subscale/confirmed by a 2nd adjacent ≥10 deterioration from BL) for EORTC QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and EORTC QLQ-HCC18 abdominal swelling, pain and fatigue, as reported by pts. Stratified Cox proportional hazards model was used to assess the magnitude of the Tx difference (HR) between arms in TTD. Results: Compliance with PRO assessments was &gt;91% from BL until wk 27 in both arms. From BL to wk 27, LSM changes in GHS/QoL, PF, role functioning (RF), QLQ-HCC18 functional/domain scores and EQ5D-5L VAS were generally similar between the two arms (Table). Treatment with len + pembro delayed deterioration of patient-reported quality of life vs len + pbo (median TTD, 11.5 vs 4.3 mo; HR, 0.80; 95% CI, 0.65-0.98). LSM score difference (95% CI) was 0.5 (-2.5, 3.4) for GHS/QoL, -1.7 (-4.5, 1.1) for PF, -1.0 (-4.9, 2.9) for RF, 1.0 (-2.2, 4.3) for abdominal swelling, 2.0 (-1.2, 5.2) for fatigue, 2.0 (-1.0, 5.0) for pain, and 0.6 (-2.0, 3.2) for EQ5D-5L VAS. Median TTD in QLQ-C30 PF (5.7 vs 9.1 mo; HR, 1.14; 95% CI, 0.93-1.41) and QLQ-HCC18 abdominal swelling (NR vs NR; HR, 1.19; 95% CI, 0.89-1.60) /fatigue (2.9 vs 2.8 mo; HR, 0.98; 95% CI, 0.81-1.19)/pain (9.6 vs 7.9 mo; HR, 0.93; 95% CI, 0.75-1.16) was similar between the arms. Conclusions: Len + pembro generally preserved HRQoL vs len + pbo in 1L for aHCC. Combined with efficacy and safety results from LEAP-002, these findings support continued development of len + pembro in HCC. Clinical trial information: NCT03713593 . [Table: see text]
Disparities in late-stage pancreatic cancer: Retrospective analysis of genomic testing and outcomes between Hispanics and non-Hispanics.
Authors: Ricardo J. Estrada-Mendizabal, Ritika Halder, Amith Rao, Ce Cheng, Isabellyana Dominguez, Sumana Veeravelli, Alejandro Recio-Boiles
Journal: Journal of Clinical Oncology (2023)

663 Background: Late-Stage Pancreatic Cancer (LS-PC) represents the 7th leading cause of cancer-related deaths worldwide. Hispanic (H) ethnicity is underrepresented in genomic studies and disparities have been demonstrated in overall treatment and outcomes. Germline, somatic tissue, and somatic liquid testing are effective tools that aid in identifying targeted genetic alterations. We comprehensively evaluated the differences in genomic testing among H and Non-Hispanic (NH) patients with LS-PC. Methods: This is a retrospective analysis of LS-PC with ductal adenocarcinoma from the University of Arizona Cancer Center from 2013 to 2021. Data collected included: patient demographics, clinical characteristics, treatment regimens, germline, somatic tissue, and somatic liquid genetic testing, and outcomes. LS was defined as unresectable and/or metastatic de novo or recurrence. Univariate comparisons used parametric and nonparametric tests as appropriate to evaluate for differences between H and NH groups. Fisher's exact tests were performed to evaluate the difference in frequency. Kaplan Meier and Cox regression analysis assessed progression-free and overall survival. Results: The analysis included 198 patients who had LS-PC with 20.7% H. 64.1%, 48.9%, and 48.9% of the patients had germline, somatic tissue, and somatic liquid testing, respectively. No significant differences were noted in baseline characteristics, treatments, and outcomes [PFS (HR 1.1, 95% CI 0.7-1.6, p=0.70) / OS (HR 1.2, 95% CI 0.7-1.9, p= 0.54)]. There was no statistically significant difference in common mutations or variants among groups. Conclusions: To our knowledge, this is the first and largest study to report LS-PC genomic and therapeutic implications in H patients. H were significantly less likely to receive germline screening and more likely to have potentially actionable pathogenic variants via somatic tissue and liquid biopsy testing. This highlights the importance of genetic testing to reveal mutations that can be targeted by clinical trials for LS-PC on minorities. Although our review revealed increased germline, somatic tissue, and somatic liquid biopsy genetic testing over time, there remains a critical need towards advancing genomic sequencing efforts to improve outcomes for LS-PC in the underrepresented H population.[Table: see text]
Association of punctate TAK1 expression with mortality in patients with microsatellite-stable colorectal cancer.
Authors: Norman James Galbraith, Sara SF Al-Badran, Phimmada Hatthakarnkul, Kathryn AF Pennel, Jean A. Quinn, Lynette Loi, Noori Maka, Colin William Steele, Campbell SD Roxburgh, Donald C. McMillan, Paul G. Horgan, Joanne Edwards
Journal: Journal of Clinical Oncology (2023)

220 Background: Microsatellite stable (MSS) colorectal cancer continues to have limited options for personalised therapeutic targets. The NFKB pathway is known to play an important role in inflammation-related carcinogenesis but has yet to be translated into therapies for the clinical patient. The aim of this study was to investigate the expression of cytoplasmic and punctate TAK1 (transforming growth factor β-activated protein kinase 1) in colorectal cancer and its relationship to immune checkpoint expression and prognosis. Methods: Patients undergoing primary colorectal cancer resection between 1997 and 2007 at Glasgow Royal Infirmary (UK) were studied for clinicopathological data and immunohistochemistry (IHC) performed on archival FFPE tissue from resected specimens. Antibodies for TAK1, PD-1, PD-L1, IKK alpha and other proteins were used for IHC, with digital analysis (QuPath) for quantification of cytoplasmic staining and punctate score for juxta-nuclear TAK1 assessment. Kaplan-Meier curves were created with log-rank test to determine survival. Cox-proportional hazards regression were used to determine multivariate hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 898 patients who underwent colorectal resection were identified. Higher TAK1 punctate expression was observed in left colon and rectal cancer, compared with right sided disease (p = 0.045). MMR proficient tumours had higher frequencies of high TAK1 punctate expression (p &lt; 0.001). Both cytoplasmic and punctate TAK1 expression correlated with IKK expression (p &lt; 0.050). High cytoplasmic TAK1 expression was associated with increased PD-1 and PD-L1 expression (p &lt; 0.001). Punctate TAK1 expression was associated with worse survival (p = 0.037). These differences were accentuated in patients with MSS status (p = 0.016). On multivariate analysis, high punctate TAK1 expression remained a predictor of worse cancer-specific survival (HR 1.843, CI 1.129-2.956, p = 0.011). Conclusions: TAK1 expression was associated with MSI status, and higher TAK1 expression correlates with upregulated PD-1 and PD-L1 expression. High punctate TAK1 expression predicted cancer-specific survival. In subgroup analysis of MSS patients, high punctate TAK1 expression was associated with poor survival. Further interrogation into this pathway may identify inflammation-related therapeutic targets in MSS patients with colorectal cancer.